AFF3, a susceptibility factor for autoimmune diseases, is a molecular facilitator of immunoglobulin class switch recombination

Abstract

Immunoglobulin class switch recombination (CSR) plays critical roles in controlling infections and inflammatory tissue injuries. Here, we show that AFF3 , a candidate gene for both rheumatoid arthritis and type 1 diabetes, is a molecular facilitator of CSR with an isotype preference. Aff3 -deficient mice exhibit low serum levels of immunoglobulins, predominantly immunoglobulin G2c (IgG2c) followed by IgG1 and IgG3 but not IgM. Furthermore, Aff3 -deficient mice show weak resistance to Plasmodium yoelii infection, confirming that Aff3 modulates immunity to this pathogen. Mechanistically, the AFF3 protein binds to the IgM and IgG1 switch regions via a C-terminal domain, and Aff3 deficiency reduces the binding of AID to the switch regions less efficiently. One AFF3 risk allele for rheumatoid arthritis is associated with high mRNA expression of AFF3 , IGHG2 , and IGHA2 in human B cells. These findings demonstrate that AFF3 directly regulates CSR by facilitating the recruitment of AID to the switch regions.

DOT1L limits RNAPII promoter-proximal pause release thus enabling Activation Induced Deaminase activity genome-wide

“…1E, 1F), suggesting it functions differently in CSR. We conclude that Dot1l, Mllt10, and Mllt1 as well as the scaffold subunits of the SEC (Aff1), and SEC-L3 (Aff3) 31 , are proximal to AID in the nucleus and are participate in CSR.…”

“…ChIPs were performed as per standard protocol 31 . Briefly, for ChIPs from stimulated CH12-F3, 4x10 5 cells were stimulated in 10mL of media with CIT and cross-linked with 1% formaldehyde for 8 minutes at room temperature, at 16h post-stimulation.…”

A robust primary liver cancer subtype related to prognosis and drug response based on a multiple combined classifying strategy

“…Homeobox D9 (HOXD9) regulated and controlled many cells growth, and its overexpression can significantly enhance the migration, invasion and metastasis of hepatocellular carcinoma cells [ 44 ]. ALF Transcription Elongation Factor 3 (AFF3) was a susceptibility gene of autoimmune diseases [ 45 ]. Compared with normal samples, this gene was low expressed in gastric cancer, but its high expression was associated with poor prognosis of gastric cancer patients [ 46 ].…”

New insights into the role of immunity and inflammation in diabetic kidney disease in the omics era

“…The largest GWAS study of the risk loci for subjects with T1DM was launched by GENIE, in which they found two single nucleotide polymorphisms (SNPs) were associated with ESRD: one in AFF3 gene ( P = 1.2 × 10 −8 ) and the other between the genes RGMA and MCTP2 ( P = 2.0 × 10 −9 ) ( 32 ). The mRNA expression of AFF3 is known to be relatively restricted to lymphocytes and brain tissues, encoding the AFF3 protein that facilitates the class switch recombination in B lymphocytes ( 33 ). AFF3 was also recognized as a candidate gene for rheumatoid arthritis, suggesting its modulatory effects on the immune system and inflammation that may contribute to the development of DKD ( 34 ).…”